Antimycotic agent and fungicidal agent

ABSTRACT

A novel ketene S,S-acetal derivative which is useful as an antimycotic agent and an agricultural chemical of fungicidal, plant growth regulating or insecticidal properties represented by the general formula (I): ##STR1## wherein R represents a hydrogen atom; an alkyl group having 1 to 8 carbon atoms; a cycloalkyl group having 3 to 6 carbon atoms; a methylene group; a lower alkenyl group; a lower alkyl group substituted by a halogen atom, a cyano group, a lower alkoxyl group, a lower alkylthio group; a carbamoyl group, an acyl group, or an alkenoyloxy group; a phenyl group represented by ##STR2## (in which R 1  represents a hydrogen atom, a halogen atom, a straight or branched chain lower alkyl group, a lower alkoxyl group which may be substituted by one or more halogen atoms, a phenoxy group or a methylenedioxy group, and m represents an integer of 1 to 3); a benzyl group; a methylenedioxybenzyl group; a phenoxyalkyl group; a phenoxyalkyl group substituted by a halogen atom; a naphthyl group; or a substituted or unsubstituted pyridyl group.

This is a division of application Ser. No. 786,123 filed Oct. 10, 1985.

BACKGROUND OF THE INVENTION

This invention relates to a novel ketene S,S-acetal derivatives whichare useful as antimycotic agents and agricultural chemicals.

More particularly, this invention relates to ketene S,S-acetalderivatives represented by the general formula (I): ##STR3## wherein Rrepresents a hydrogen atom; an alkyl group having 1 to 8 carbon atom; acycloalkyl group having 3 to 6 carbon atoms; a methylene group; a loweralkenyl group; a lower alkyl group substituted by a halogen atom, acyano group, a lower alkoxy group, a lower alkylthio group, a carbamoylgroup, an acyl group, or an alkenoyloxy group; a phenyl grouprepresented by ##STR4## (in which R₁ represents a hydrogen atom, ahalogen atom, a straight or branched chain lower alkyl group, a loweralkoxyl group which may be substituted by one or more halogen atoms, aphenoxy group or a methylenedioxy group, and m represents an integer of1 to 3); a benzyl group; a methylenedioxybenzyl group; a phenoxyalkylgroup; a phenoxyalkyl group substituted by a halogen atom; a naphthylgroup; or a substituted or unsubstituted pyridyl group.

SUMMARY OF INVENTION

The present inventors have devoted themselves to research in order toinvent a novel ketene S,S-acetal derivative, and have consequently foundthat compounds represented by the general formula (I) are novelcompounds not described in literatures and are useful as antimycoticagents and agricultural chemicals; in particular, not only fungicidesand plant growth regulators but also insecticides, whereby thisinvention has been accomplished.

The substituent R in the above general formula (I) includes hydrogenatom; straight or branched chain alkyl groups such as methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl,i-pentyl, neo-pentyl, n-hexyl, n-octyl and the like; cycloalkyl groupssuch as cyclopropyl, cyclohexyl and the like; methylene group; loweralkenyl groups such as vinyl, allyl and the like; lower alkyl groupssubstituted by a halogen atom such as chloromethyl, dichloroethyl andthe like; lower alkyl groups substituted by a cyano group such ascyanomethyl and the like; lower alkyl groups substituted by a loweralkoxyl such as methoxymethyl, methoxyethyl and the like or a loweralkylthio group such as methylthiomethyl and the like; lower alkyl groupsubstituted by carbamoyl group such as carbamoylmethyl and the like;lower alkyl groups substituted by an acyl group; lower alkyl groupssubstituted by an alkenoyloxy groups such as acryloylmethyl and thelike; phenyl groups represented by ##STR5## (in which R₁ represents ahydrogen atom, a halogen atom, a straight or branched chain lower alkylgroup, a lower alkoxyl group which may be substituted by one or morehalogen atoms, a phenoxy group or a methylenedioxy group, and mrepresents an integer of 1 to 3); a benzyl group; a methylenedioxybenzylgroup; a phenoxyalkyl group such as phenoxymethyl and the like; aphenoxyalkyl group substituted by a halogen atom; naphthyl group;substituted or unsubstituted pyridyl group; etc.

DETAILED DESCRIPTION OF INVENTION

The compound represented by the general formula (I) of this inventioncan be synthesized, for example, by the process shown below: ##STR6##wherein R is as defined above, and X represents a halogen atom, amesyloxy or a tosyloxy group. That is to say, the compound representedby the general formula (I) can be obtained by reacting1-cyanomethylimidazole represented by the structural formula (II) withcarbon disulfide in the presence of a base and a solvent to form anintermediate represented by the structural formula (IV), and reactingthe intermediate with a compound represented by the general formula(III) without isolating the same.

As the solvent usable in the invention, any solvent may be used so longas it does not inhibit the progress of the reaction, and there can beexemplified, for example, alcohols such as methanol, ethanol,isopropanol and the like, dimethylsulfoxide, dimethylformamide,hexamethylenephosphoroamide, water, etc. These solvents can be usedalone or as a mixture thereof.

As the base usable in this invention, there can be exemplified sodiumcarbonate, potassium carbonate, sodium hydrogencarbonate, potassiumhydrogencarbonate, sodium hydroxide, potassium hydroxide, potassiumt-butoxide, etc. These can be used in solid state or in solution.

Althougn it is sufficient that the reaction temperature is selected inthe range of 0° to 100° C., it is particularly preferable to carry outthe reaction at a temperature near room temperature.

It is sufficient that the reaction time is properly selected in therange of 0.5 to 24 hours.

It is sufficient that the amount of the base used is selected in therange of 2 to 4 moles per mole of 1-cyanomethylimidazole represented bythe structural formula (IV).

It is sufficient that after completion of the reaction, the reactionsolution is treated in the usual way. For example, the reaction productis extracted and separated with a suitable solvent and then can bepurified by recrystallization or column chromatography.

The compound represented by the general formula (I) is often obtained asa mixture of two kinds of the geometrical isomers shown below. ##STR7##

The aforesaid mixture of the Z and E isomers can often be isolated intothe two isomers by a suitable separation method, for example,recrystallization, chromatography or the like.

This invention includes the geometrical isomers, i.e., the E and Zisomers, and all mixtures of the two isomers in any ratio.

Typical examples of the compounds represented by the general formula (I)are shown in Table 1, but this invention is not limited thereto.

                  TABLE 1                                                         ______________________________________                                         ##STR8##                      (I)                                                                     Physical property,                                   Com-                     melting point, refractive                            pound                    index, NMR value                                     No.   R                  (TMS/CDCl.sub.3)                                     ______________________________________                                        1     H                  Melting point 126.5° C.                       2     CH.sub.3           Melting point 97.6° C.                        3     C.sub.2 H.sub.5    n.sub.D.sup.17 1.6246                                4     n-C.sub.3 H.sub.7  n.sub.D.sup.27 1.6065                                5     i-C.sub.3 H.sub.7  Melting point 86.7° C.                                                 (Z isomer)                                           6     i-C.sub.3 H.sub.7  Melting point 55.8° C.                                                 (E isomer)                                           7     n-C.sub.4 H.sub.9  n.sub.D.sup.27 1.5830                                8     i-C.sub.4 H.sub.9  Melting point 73.3° C.                                                 (Z isomer)                                           9     i-C.sub.4 H.sub.9  Melting point 118.1° C.                                                (F isomer)                                           10    s-C.sub.4 H.sub.9  n.sub.D.sup.16 1.6011 (Z isomer)                     11    s-C.sub.4 H.sub.9  n.sub.D.sup.16 1.6089 (E isomer)                     12    t-C.sub.4 H.sub.9  Melting point 151.7° C.                       13    n-C.sub.5 H.sub.11 n.sub.D.sup.16.5 1.5931 (Z isomer)                   14    n-C.sub.5 H.sub.11 n.sub.D.sup.16.5 1.5949 (E isomer)                   15    i-C.sub.5 H.sub.11 Melting point 74.3° C.                                                 (Z isomer)                                           16    i-C.sub.5 H.sub.11 Melting point 111.4° C.                                                (E isomer)                                           17    neo-C.sub.5 H.sub.11                                                                             Melting point 96.2° C.                                                 (Z isomer)                                           18    neo-C.sub.5 H.sub.11                                                                             Melting point 107.7° C.                                                (E isomer)                                           19    n-C.sub.6 H.sub.13 n.sub.D.sup.17 1.5908 (Z isomer)                     20    n-C.sub.6 H.sub.13 Melting point 48.2° C.                                                 (E isomer)                                           21                                                                                   ##STR9##          Melting point 113.9° C. (Z isomer)            22                                                                                   ##STR10##         Melting point 103.8° C. (E isomer)            23    CH.sub.2           Melting point 115.7° C.                       24    CHCH.sub.2         n.sub.D.sup.27 1.6422                                25    CH.sub.2 Cl        Melting point 96.2° C.                        26    CHClCH.sub.2 Cl    n.sub.D.sup.16 1.6103                                27    CH.sub.2 CN        n.sub.D.sup.18  1.6167                               28    CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.3                                                             n.sub.D.sup.24 1.6009                                29    CH.sub.2 CSH.sub.3 n.sub.D.sup.13.5 1.6412                              30    CH.sub.2 CONH.sub.2                                                                              Viscous oily substance                                                        3.64 (m, 2H), 4.20 (m,                                                        3H), 5.27 (br, 2H)                                                            6.96, 7.05, 7.52 (1H on                                                       hetero ring for each)                                31    CH.sub.2 CH.sub.2 COCH.sub.3                                                                     n.sub.D.sup.18 1.6086                                32    CH.sub.2 O.sub.2 CCHCH.sub.2                                                                     n.sub.D.sup.18 1.6082                                33                                                                                   ##STR11##         n.sub.D.sup.24 1.6417                                34                                                                                   ##STR12##         Melting point 119.4° C. (Z isomer)            35                                                                                   ##STR13##         Melting point 141.5° C. (E isomer)            36                                                                                   ##STR14##         n.sub.D.sup.24 1.6083                                37                                                                                   ##STR15##         Viscous oily substance (Z isomer) 3.54-4.20 (m,                               2H), 5.69 (DD, 1H), 7.00-7.75 (m, 7H)                38                                                                                   ##STR16##         Viscous oily substance (E isomer) 3.45-4.10 (m,                               2H), 5.76 (dd, 1H) 7.00-7.85 (m, 7H)                 39                                                                                   ##STR17##         Viscous oily substance (z isomer) 3.6-4.0 (m,                                 2H), 5.22 (dd, 1H) 6.9-7.81 (m, 7H)                  40                                                                                   ##STR18##         Melting point 148.8° C. (E isomer)            41                                                                                   ##STR19##         Viscous oily substance (Z isomer)                    42                                                                                   ##STR20##         Melting point 119° C. (E isomer)              43                                                                                   ##STR21##         Viscous Oily substance 3.6-3.9 (m, 2H), 5.1-5.5                               (m, 1H) 6.9-7.8 (m, 7H)                              44                                                                                   ##STR22##         n.sub.D.sup.18 1.6313 (Z isomer)                     45                                                                                   ##STR23##         Melting point 123.3° C. (E isomer)            46                                                                                   ##STR24##         n.sub.D.sup.24 1.6360                                47                                                                                   ##STR25##         n.sub.D.sup.16 1.6196                                48                                                                                   ##STR26##         Viscous oily substance (Z isomer)                    49                                                                                   ##STR27##         Viscous oily substance (E isomer) 3.71 (d, 2H),                               3.82 (s, 3H), 5.68 (t, 1H) 6.87, 7.00, 6.72 (1H,                              for each, H on azole ring) 7.00-7.60 (m, 4H)         50                                                                                   ##STR28##         Viscous oily substance (Z isomer) 3.75 (d, 2H),                               3.77 (s, 3H), 5.17 (t, 1H), 6.74-7.60 (m, 7H)        51                                                                                   ##STR29##         Viscous oily substance (E isomer) 3.67 (d, 2H),                               3.80 (s, 3H), 5.24 (t, 1H), 6.70-7.65 (m, 7H)        52                                                                                   ##STR30##         Melting point 110.5° C. (Z isomer)            53                                                                                   ##STR31##         Melting point 100.4° C. (E isomer)            54                                                                                   ##STR32##         Viscous oily substance (Z isomer)                    55                                                                                   ##STR33##         Viscous oily substance (E isomer) 3.42 (dd, 1H),                              4.43 (t, 1H), 6.16 (dd, 1H), 7.18-7.40 (m, 3H),                               6.98, 7.08, 7.56 (1H for each, H on azole ring)      56                                                                                   ##STR34##         Viscous oily substance 3.6-3.9 (m, 2H), 5.0-5.4                               (m, 1H), 6.9-7.8 (m, 6H)                             57                                                                                   ##STR35##         Viscous oily substance 3.64, 3.72 (d, 2H for                                  each), 5.11, 5.19 (t, 1H for each), 5.92, 5.95                                (s,  2H for each), 6.60.6.95 (m, 3H), 7.00,                                   7.08, 7.53 (1H for each, H on azole ring)            58                                                                                   ##STR36##         Melting point 187.5° C. (Z isomer)            59                                                                                   ##STR37##         Melting point 214.0° C. (E isomer)            60                                                                                   ##STR38##         Melting point 102.7° C.                       61                                                                                   ##STR39##         n.sub.D.sup.17 1.6258                                62                                                                                   ##STR40##         n.sub.D.sup.18 1.6315                                63                                                                                   ##STR41##         n.sub.D.sup.18 1.6213                                64                                                                                   ##STR42##         Melting point 135.0° C.                       65                                                                                   ##STR43##         Viscous oily substance 3.65-4.38 (m, 2H),                                     5.22-5.60 (m, 1H), 7.00-7.95 (m, 6H), 8.54-8.76                               (m, 1H)                                              66                                                                                   ##STR44##         Viscous oily substance 3.75 (m, 2H), 5.20 (m,                                 1H), 6.80-7.80 (m, 7H)                               67                                                                                   ##STR45##         n.sub.D.sup.18.5 1.6063                              68                                                                                   ##STR46##         Viscous oily substance (Z isomer) 3.83 (m, 2H),                               5.46 (dd, 1H), 6.70-7.80 (m, 6H)                     69                                                                                   ##STR47##         Viscous oily substance (E isomer) 3.75 (m, 2H),                               5.52 (dd, 1H), 6.60-7.80 (m, 6H)                     70                                                                                   ##STR48##         n.sub.D.sup.17.5 1.6358 (E isomer)                   71                                                                                   ##STR49##         n.sub.D.sup.17.5 1.6458 (Z isomer)                   72                                                                                   ##STR50##         Viscous oily substance (Z isomer) 3.83 (m, 2H),                               5.59 (dd, 1H), 6.75-7.70 (m, 6H)                     73                                                                                   ##STR51##         m.p. 146-152° C. (E isomer)                   74                                                                                   ##STR52##         Viscous oily substance (Z isomer) 3.38 (m, 2H),                               5.42 (dd, 1H), 6.90-7.70 (m, 6H)                     75                                                                                   ##STR53##         m.p. 114-117° C. (E isomer)                   76                                                                                   ##STR54##         n.sub.D.sup.22.0 1.6401                              77                                                                                   ##STR55##         n.sub.D.sup.22.0 1.6262                              78                                                                                   ##STR56##         n.sub.D.sup.25.5 1.6432                              79                                                                                   ##STR57##         n.sub.D.sup.25.5 1.6332                              ______________________________________                                    

Preferred compounds are these in which R represents a lower alkyl group,a lower alkyl group substituted by a lower alkoxyl or alkylthio group,or ##STR58## in which R₁ represents a halogen atom, especially chlorineor bromine atom, or a straight or branched chain lower alkyl group,especially methyl, and m represents an integer of 1 to 3.

Examples of this invention are shown below.

EXAMPLE 1 Synthesis of2-(1-imidazolyl)-2-(4-isobutyl-1,3-dithiolan-2-ylidene)acetonitrile(Compound Nos. 8 and 9)

To a mixed solution of 0.55 g (0.005 mole) of 1-cyanomethylimidazole,0.4 g (0.005 mole) of carbon disulfide and 10 ml of dimethyl sulfoxidewas added 0.8 g (0.014 mole) of potassium hydroxide powder withstirring, and the reaction was carried out at room temperature for 1hour. Then, 1.5 g (0.006 mole) of 1,2-dibromo-4-methylpentane was addeddropwise with stirring, and the resulting solution was subjected toreaction for 2 hours. After completion of the reaction, 20 ml of waterwas added to the reaction solution, after which the resulting mixturewas subjected to extraction with ethyl acetate, and the organic layerwas washed with water and dried. The solvent was distilled off and theresidue was purified by silica gel chromatography to obtain 0.45 g ofthe Z isomer and 0.3 g of the E isomer individually in the form ofcolorless crystals.

The Z isomer (Compound No. 8): melting point 73.3° C., yield 34%.

The E isomer (Compound No. 9): melting point 118.1° C., yield 23%.

EXAMPLE 2 Synthesis of2-(1-imidazolyl)-2-(4-chloromethyl-1,3-dithiolan-2-ylidene)acetonitrile(Compound No. 25)

To a mixed solution of 0.55 g (0.005 mole) of 1-cyanomethylimidazole,0.4 g (0.005 mole) of carbon disulfide and 10 ml of dimethyl sulfoxidewas added 0.8 g (0.014 mole) of potassium hydroxide power with stirring,and the reaction was carried out at room temperature for 1 hour. Then,1.4 g (0.006 mole) of 1,2-dibromo-3-chloropropane was added dropwisewith stirring, and the resulting solution was subjected to reaction for2 hours. After completion of the reaction, 20 ml of water was added tothe reaction solution, after which the resulting mixture was subjectedto extraction with ethyl acetate, and the organic layer was washed withwater and dried. The solvent was distilled off and the residue waspurified by silica gel chromatography and recrystallized from ethylacetate-n-hexane to obtain 0.8 g of the desired compound in the form ofcolorless crystals: melting point 96.2° C., yield 62%.

EXAMPLE 3 Synthesis of2-(1-imidazolyl)-2-(4-methylidene-1,3-dithiolan-2-ylidene)acetonitrile(Compound No. 23)

In 10 ml of tetrahydrofuran were dissolved 0.52 g (0.002 mole) of the2-(1-imidazolyl)-2-(4-chloromethyl-1,3-dithiolan-2-ylidene)acetonitrileobtained in Example 2 and 0.31 g of 1,8-diazabicyclo-[5,4,0]-7-undecene,and the reaction was carried out with heating under reflux for 1 hour.After the reaction solution was allowed to cool, the deposited salt wasseparated by filtration and the filtrate was concentrated to obtaincrude crystals, which were then recrystallized from ethylacetate-n-hexane to obtain 0.35 g of the desired compound in the form ofcrystals: melting point 115.7° C., yield 79%.

EXAMPLE 4 Synthesis of2-(1-imidazolyl)-2-[4-(2,4-dichlorophenyl)-1,3-dithiolan-2-ylidene]acetonitrile(Compound Nos. 52 and 53)

To a mixed solution of 0.55 g (0.005 mole) of 1-cyanomethylimidazole,0.4 g (0.005 mole) of carbon disulfide and 10 ml of dimethyl sulfoxidewas added 0.8 g (0.014 mole) of potassium hydroxide powder withstirring, and the reaction was carried out at room temperature for 1hour. Then, 2.0 g (0.006 mole) of 2',4'-dichloro-1,2-dibromoethylbenzenewas added dropwise with stirring, and the resulting solution wassubjected to reaction for 2 hours. After completion of the reaction, 20ml of water was added to the reaction solution, and the resultingmixture was subjected to extraction with ethyl acetate, and the organiclayer was washed with water and dried. The solvent was distilled off andthe residue was purified by silica gel chromatography to obtain 0.25 gof the Z isomer and 0.5 g of the E isomer individually in the form of ayellow viscous substance: yield (total yield of the Z and E isomers)42%, melting points 110.5° C. (the Z isomer) and 100.4° C. (the Eisomer).

EXAMPLE 5 Synthesis of2-(1-imidazolyl)-2-[4-(2-isopropylphenyl)-1,3-dithiolan-2-ylidene]acetonitrile(Compound No. 47)

To mixed solution of 0.55 g (0.005 mole) of 1-cyanomethylimidazole, 0.4(0.005 mole) of carbon disulfide and 10 ml of dimethylformamide wasadded 0.8 g (0.014 mole) of potassium hydroxide powder, and the reactionwas carried out with stirring at room temperature for 1 hour. Then, 1.8g (0.006 mole) of 2'-isopropyl-1,2-dibromoethylbenzene was addeddropwise with stirring, and the resulting solution was subjected toreaction for another 2 hours. After completion of the reaction, 20 ml ofwater was added to the reaction solution, and the resulting mixture wassubjected to extraction with ethyl acetate, and the organic layer waswashed with water and dried. The solvent was distilled off and theresidue was purified by silica gel chromatography to obtain the desiredcompound in the form of a light-yellow oily substance: n_(D) ¹⁶ 1.6196,yield 34%.

EXAMPLE 6 Synthesis of2-(1-imidazolyl)-2-[4-(2-chlorophenyl)-1,3-dithiolan-2-ylidene]acetonitrile(Compound Nos. 34 and 35)

To a mixed solution of 2.2 g (0.02 mole) of 1-cyanomethylimidazole, 1.60g (0.02 mole) of carbon disulfide and 10 ml of dimethyl sulfoxide wasadded 3.0 g (0.05 mole) of potassium hydroxide powder, and the reactionwas carried out with stirring at room temperature for 1 hour. Then, 4.2g (0.02 mole) of 2'-chloro-(1,2-dichloroethyl)benzene was added dropwisewith stirring, and the resulting solution was subjected to reaction foranother 2 hours. After completion of the reaction, 20 ml of water wasadded to the reaction solution, after which the resulting mixture wassubjected to extraction with ethyl acetate, and the organic layer waswashed with water and dried. The solvent was distilled off and theresidue was purified by silica gel chromatography to obtain 2.0 g of theZ isomer and 2.4 g of the E isomer individually in the form oflight-yellow crystals.

The Z isomer: melting point 119.4° C., yield 31%.

The E isomer: melting point 141.5° C., yield 38%.

EXAMPLE 7 Synthesis of2-(1-imidazolyl)-2-[4-(2-chlorophenyl)-1,3-dithiolan-2-ylidene]acetonitrile(Compound Nos. 34 and 35)

To a mixed solution of 2.2 g (0.02 mole) of 1-cyanomethylimidazole, 1.60g (0.02 mole) of carbon disulfide and 10 ml of dimethyl sulfoxide wasadded 3.0 g (0.05 mole) of potassium hydroxide powder, and the reactionwas carried out with stirring at room temperature for 1 hour. Then, 6.0g (0.02 mole) of 2'-chloro-(1,2-dibromoethyl)benzene was added dropwisewith stirring, and the resulting solution was subjected to reaction foranother 2 hours. After completion of the reaction, 20 ml of water wasadded to the reaction solution, after which the resulting mixture wassubjected to extraction with ethyl acetate, and the organic layer waswashed with water and dried. The solvent was distilled off and theresidue was purified by silia gel chromatography to obtain 0.3 g of theZ isomer and 1.3 g of the E isomer individually in the form oflight-yellow crystals.

The Z isomer: melting point 119.4° C., yield 5%.

The E isomer: melting point 141.5° C., yield 20%.

EXAMPLE 8 Synthesis of2-(1-imidazolyl)-2-[4-(2-chlorophenyl)-1,3-dithiolan-2-ylidene]acetonitrile(Compound Nos. 34 and 35)

To a mixed solution of 2.2 g (0.02 mole) of 1-cyanomethylimidazole, 1.60g (0.02 mole) of carbon disulfide and 10 ml of dimethyl sulfoxide wasadded 3.0 g (0.05 mole) of potassium hydroxide powder, and the reactionwas carried out with stirring at room temperature for 1 hour. Then, 6.6g (0.02 mole) of 2'-chloro-(1,2-dimesyloxyethyl)benzene was addeddropwise with stirring, and the resulting solution was subjected toreaction for another 2 hours. After completion of the reaction, 20 ml ofwater was added to the reaction solution, after which the resultingmixture was subjected to extraction with ethyl acetate, and the organiclayer was washed with water and dried. The solvent was distilled off andthe residue was purified by silica gel chromatography to obtain 1.3 g ofthe Z isomer and 1.8 g of the E isomer individually in the form oflight-yellow crystals.

The Z isomer: melting point 119.4° C., yield 20%.

The E isomer: melting point 141.5° C., yield 28%.

The compounds of this invention are antimycotic agents useful forpreventing fungous infection of human beings and animals. For example,these compounds can be used for curing mycoses such as local mycoticinfection, mucosal mycotic infection, systemic mycotic infection and thelike which are caused by Dermatophytes such as Microsporum,Epidermophyton, Trichophyton and the like and Candida.

The compounds of this invention can be mixed with conventionalchemotherapeutically acceptable diluents or carriers and if desired,other excipients, and can be used in pharmaceutical forms such assolutions, creams, suppositories, ointments, tablets, etc.

When used as antimycotic agents, the compounds of this invention can beused as local liniments in pharmaceutical forms such as creams,ointments, solution, etc. When they are used in the form of an endermicsolution, their practical concentration is considered to be suitably0.1% or more.

The present drugs may be used, of course, in an admixture with otherantibacterial agents such as amphotericin B, nystatin, trichomycin,variotin, clotrimazole and the like.

Further, the compounds of this invention are useful as agricultural andhorticultural fungicides. For example, they are very effective againstvarious phytopathogenic diseases, e.g., rice blast (Piricularia oryzae);powdery mildew of barley and wheat (Erysiphe graminis), and otherpowdery mildews of various host plants such as that of cucumber(Sphaerotheca fulginea), that of apple (Podosphaera leucotricha) andthat of grape (Uncinula necator); rust of wheat (Puccinia vecondita);Crown rust of oats (Puccinia coronate) and rust of other host plants:late blight of tomato (phytophthora capsici) and phytophthora rot ofother host plants; etc.

When the compound of this invention is used as active ingredient in anagricultural and a horticultural fungicide, the fungicide is preparedinto a formulation suitable for use in a conventional manner as anagricultural chemical. For example, the fungicide is prepared in theform of dust, granules, fine granules, wettable powder, emulsifiableconcentrate, oily solution, aerosol, floating dust, fumigants,preparations suitable for vaporizing the active ingredient by heat orother physical means, tablets or the like by mixing the compound of theinvention with adjuvants, and is applied to stalks and leaves ofvegetables, flowering plants, crops for industrial use, fruit trees,other trees and the like as it is or after diluted to a suitable volumewith water. Although in this invention the dosage of the activeingredient varies depending on the kind of the compound, plant to betreated, the way of using, and the like, it can be selected in the rangeof 5 to 500 g per 10 ares.

When applied, the compound of this invention can also be used inadmixture with or in combination with other agricultural chemicals,fertilizers, plant nutrients and the like which can be used similarly tothe compound.

For example, when a phytopathogenic disease is controlled by using anagricultural and horticultural fungicide comprising the compound of thisinvention as active ingredient, the fungicide can be made into amultiple-purpose preventing and curing agent by mixing therewith anagent for preventing and curing other diseases and/or vermin insectswhich break out simultaneously with aforesaid disease.

Next, some test examples and formulation examples are given below inorder to demonstrate the usefulness of the compounds of this invention,but this invention is not intended to be limited thereto.

TEST EXAMPLE 1 Test for antifungal activity against Trichophytonmentagrophytes

In 1 liter of water were dissolved 10 g of peptone and 4.0 g of glucoseand the resulting solution was adjusted to pH 6.0, after which a drugcontaining 50 ppb (1% DMSO solution) of each active ingredient wasadded. Into a 3.5 φ cm Petri dish was poured 30 ml of the thus obtainedSabouraud medium to prepare an agar plate. Then, the inoculum of thefungus precultured was poured onto the plate in an amount of 0.1 ml perPetri dish. Thus prepared plates were incubated at 28° C. for 4-6 days.The test was carried out in duplication for each compound and theresults per dish evaluated macroscopically are shown in Table 2.Evaluation criterion

+ Multiplication of cells was completely inhibited.

± Multiplication of cells was inhibited.

++ White colonies were formed.

+++ The diameter of white colonied increased.

                  TABLE 2                                                         ______________________________________                                        Compound No.       Degree of growth                                           ______________________________________                                         4                 ±     +                                                 28                 ±     +                                                 33                 ±     ±                                              35                 ±     +                                                 36                 ±     ±                                              37                 ±     ±                                              38                 +        +                                                 39                 ±     ±                                              40                 ±     ±                                              41                 +        ++                                                42                 +        ±                                              43                 ±     ±                                              46                 ±     ±                                              52                 ±     ±                                              53                 ±     ±                                              59                 ±     ±                                              64                 +        +                                                 65                 +        +                                                 Control                                                                       (no compound added)                                                           ______________________________________                                    

TEST EXAMPLE 2 Curing effect test against trichophytosis which wasartificially infected in guinea pigs

Hartley strain white male guinea pigs (400 to 600 g) were used as testanimals. The hair in three spots on the back of each guinea pig wassheared and then removed in a circle having a diameter of about 3 cm byuse of depilatory cream, after which the skin in the depilated spots waslightly rubbed with sandpaper. Thus treated spots were inoculated with0.1 ml (10⁶ spores/spot) of culture of Trichophyton mentagrophytesIFO-5466 strain grown on Sabouraud glucose agar media. Each test drugprepared by using polyethylene glycol 300 as base was applied to theinoculation spots once daily for 11 consecutive days in an amount of 0.2ml per inoculation spot, starting 72 hours after the inoculation. Theevaluation was conducted by macroscopical judgement and reverse culturetest.

(a) Macroscopical judgement:

After the inoculation, the alleviation and development of symptoms inthe above-mentioned spots were observed every day for 15 days. Theresults are shown in Table 3.

0: No symptom was observed.

1: A few small erythemas were observed.

2: Erythemas were insularly scattered or fused into one, and rubefactionwas observed around them.

3: Scales were observed, and then formation of thick lesion wasobserved.

4: Lesion reached to an extreme stage with bleeding.

The results obtained are shown in Table 3.

(b) Reverse culture test

Each guinea pig was sacrified 15 days after the inoculation, after whichthe skin in the whole inoculation spots was cut off and the skin cut-offwas further cut into small pieces (about 5 mm square). The pieces thusprepared were placed on Sabouraud glucose agar medium containing 20i.u./ml of penicillin G and 40 μg/ml of streptomycin, and then culturedat 27° C. for 2 weeks. The evaulation was carried out by investigatingthe colonies. The results obtained are shown in Table 4.

                  TABLE 3                                                         ______________________________________                                        (Macroscopical judgement)                                                     Drug tested                                                                   (Concen- Days                                                                 tration) 4     5     6   7   8   9   10  11  12  13  14                                                    15                                               ______________________________________                                        Compound 53                                                                                                (1%) 0.5 1 1 1 1 1 1 1.5 1.5 1.5 2.5 2                                        (0.1%) 1 2 2 2 2.5 3 3 3.5 3.5 3.5 3.5 3.5                                    Compound 35                                                                   (1%) 1 1 1 1 1 1 1.5 1.5 1.5 1.5 3 3                                          (0.1%) 0.5 1 1.5 1.5 2 2.5 3 3.5 3.5 3.5 3.5                                  4                                                                             Compound 38                                                                   (1%) 1 1.5 1.5 1 1 1 1.5 2 2 2 2 2                                            (0.1%) 0.5 2 2 2 2.5 2.5 3 3 3.5 3.5 3.5 4                                    Tolnaftate                                                                    (1%) 1 1 1 1.5 1 1 1.5 2 2.5 2.5 3.5 3.5                                      (0.1%) 0 1.5 1.5 2 2.5 3 3 3 3 3 3 3                                          Control 1 2 2 2 3 3.5 3.5 3.5 3.5 4 4 4                                       (No                                                                           compound                                                                      treated)                                         ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                        (Results of reverse culture test)                                                               Concentration                                               Drug Tested         1%      0.1%                                              ______________________________________                                        Compound 53         0/20    7/20                                              Compound 35         0/20    6/20                                              Compound 38         0/20    6/20                                              Tolnaftate          0/20    16/20                                             Control             20/20                                                     (No compound                                                                  treated)                                                                      ______________________________________                                    

TEST EXAMPLE 3 Controlling Effects on Powdery Mildew of Barley

Young barley plants (variety: Kanto No. 6, 2-leaf stage) cultivated inthe porcelain pots (12 cm in diameter) were inoculated by conidia ofErysiphe graminis graminis F.Sp. hordei, the causal fungus of powderymildew. The day after inoculation, the plants were treated on the turntable by spraying solutions (200 ppm) of the present compounds by spraygun. The treated plants were kept at 25° C. for 6 days in a greenhouseand the development of lesions was assessed. The controlling effects ofthe compounds were calculated in comparison with the untreated plots.

The criteria for the controlling effects are:

4; 100-95% control

3; 94-80% control

2; 79-60% control

1; 59-0% control

The results are shown in Table 5.

                  TABLE 5                                                         ______________________________________                                        Com-  Concen-   Control- Com-   Concen-                                                                              Control-                               pound tration   ling     pound  tration                                                                              ling                                   No.   (ppm)     effects  No.    (ppm)  effects                                ______________________________________                                        1     200       3        38     200    4                                      3     "         4        42     "      4                                      5     "         4        43     "      4                                      8     "         4        45     "      4                                      9     "         4        46     "      4                                      12    "         3        47     "      4                                      15    "         4        48     "      4                                      17    "         4        50     "      4                                      20    "         4        53     "      4                                      21    "         4        54     "      4                                      22    "         4        56     "      4                                      24    "         4        57     "      4                                      25    "         4        58     "      4                                      26    "         4        61     "      4                                      27    "         2        62     "      4                                      28    "         4        64     "      4                                      29    "         4        65     "      4                                      30    "         2        67     "      4                                      32    "         2        72     "      4                                      33    "         4        75     "      4                                      34    "         4        76     "      4                                      35    "         4        77     "      4                                      36    "         4        78     "      4                                      37    "         4        79     "      4                                      ______________________________________                                    

TEST EXAMPLE 4 Controlling Effects on Seen-borne Fusarium

Cucumber seeds infested with Fusarium oxysporum f.sp. cucumerinum weresoaked in solutions (200 ppm) of the present compounds for 20 hr. Thetreated seeds were then placed on the selective medium for Fusarium spp.(Komada medium). After a week-incubation at 25° C., the mycelial growtharound the treated seeds was assessed and the controlling effects werecalculated in comparison with untreated plots. The criteria forcontrolling effects are as same as in Test Example 3.

The results are shown in Table 6.

                  TABLE 6                                                         ______________________________________                                        Com-  Concen-   Control- Com-   Concen-                                                                              Control-                               pound tration   ling     pound  tration                                                                              ling                                   No.   (ppm)     effects  No.    (ppm)  effects                                ______________________________________                                        3     200       4        52     200    4                                      4     "         4        53     "      4                                      6     "         4        54     "      4                                      7     "         4        55     "      4                                      10    "         4        56     "      4                                      11    "         4        57     "      4                                      13    "         4        58     "      3                                      16    "         4        60     "      4                                      18    "         4        61     "      4                                      20    "         4        63     "      4                                      21    "         4        64     "      4                                      24    "         3        65     "      4                                      26    "         2        66     "      4                                      29    "         4        67     "      2                                      33    "         4        68     "      4                                      35    "         4        69     "      4                                      37    "         4        70     "      4                                      39    "         4        71     "      4                                      40    "         4        73     "      4                                      44    "         4        75     "      4                                      47    "         4        76     "      4                                      49    "         4        77     "      4                                      50    "         4        78     "      4                                      51    "         4        79     "      4                                      ______________________________________                                    

The recipes shown below as Formulation Examples 1 to 3 are for medicalpurposes. For these purposes, the various adjuvants and constituents tobe used should be of pharmaceutically acceptable grade. In FormulationExamples 1 to 3, all parts are by weight.

FORMULATION EXAMPLE 1

    ______________________________________                                        Compound 35        1 part                                                     Polyethylene glycol 300                                                                          95 parts                                                   ______________________________________                                    

These ingredients are mixed to prepare an endermic solution.

FORMULATION EXAMPLE 2

    ______________________________________                                        Compound 53         2 parts                                                   Polyethylene glycol 400                                                                          40 parts                                                   Polyethylene glycol 1500                                                                         58 parts                                                   ______________________________________                                    

These ingredients are mixed with heating to obtain a solution, which isthen colled to prepare an ointment.

FORMULATION EXAMPLE 3

    ______________________________________                                        Copmpound 38     2 parts                                                      1,2-Propanediol  5 parts                                                      Glycerol stearate                                                                              5 parts                                                      Spermaceti       5 parts                                                      Isopropyl myristate                                                                            10 parts                                                     Polysorbate 60   4 parts                                                      ______________________________________                                    

A mixture of them is heated and then cooled, after which 69 parts ofwater is added with stirring to prepare cream.

In addition to the pharmaceutical formulations described above,preparation in pharmaceutically usable forms such as injections, tabletsand the like is possible.

The recipes shown in Formulation Examples 4 to 7 are for agriculturalchemicals. In these examples, all parts are by weight as in FormulationExamples 1 to 3.

FORMULATION EXAMPLE 4 Wettable Powder

    ______________________________________                                        Compound 12        50 parts                                                   Mixture of diatomaceous                                                                          45 parts                                                   earth and clay                                                                Polyoxyethylene nonyl-                                                                            5 parts                                                   phenyl ether                                                                  ______________________________________                                    

These ingredients are homogeneously mixed and then pulverized to preparea wettable powder.

FORMULATION EXAMPLE 5 Emulsifiable Concentrate

    ______________________________________                                        Compound 23         20 parts                                                  Tetrahydrofuran     20 parts                                                  Xylene              45 parts                                                  Mixture of polyoxyethylene                                                                        15 parts                                                  nonylphenyl ether and alkyl                                                   benzenesulfonate                                                              ______________________________________                                    

These ingredients are homogeneously mixed to prepare an emulsifiableconcentrate.

FORMULATION EXAMPLE 6 Dust

    ______________________________________                                        Compound 29        4 parts                                                    Mixture of diatomaceous                                                                          95 parts                                                   earth, clay and talc                                                          Calcium stearate   1 part                                                     ______________________________________                                    

These ingradients are homogeneously mixed and then pulverized to preparea dust.

FORMULATION EXAMPLE 7 Granules

    ______________________________________                                        Compound 46          3 parts                                                  Mixture of bentonite and clay                                                                      92 parts                                                 Calcium lignin sulfonate                                                                           5 parts                                                  ______________________________________                                    

These ingredients are homogeneously mixed and then pulverized, afterwhich an adequate amount of water is added, and the resulting mixture issufficiently kneaded and then granulated to prepare granules.

What is claimed is:
 1. A fungicidal composition for controllingphytopathogenic fungi comprising a fungicidally effective amount of aketene S,S-acetal derivative represented by the general formula (I):##STR59## wherein R represents a hydrogen atom; an alkyl group having 1to 8 carbon atoms; a cycloalkyl group having 3 to 6 carbon atoms; amethylene group; a lower alkenyl group; a lower alkyl group substitutedby a halogen atom; a cyano group, a lower alkoxyl group, a loweralkylthio group, a carbamoyl group, a lower alkanoyl group, or analkenoyloxy group; a phenyl group represented by ##STR60## (in which R₁represents a hydrogen atom, a halogen atom, a straight or branched chainlower alkyl group, a lower alkoxyl group which may be substituted by oneor more halogen atoms, a phenoxy group or a methylenedioxy group, and mrepresents an integer of 1 to 3); a benzyl group, a methylenedioxybenzylgroup; a phenoyalkyl group; a phenoxyalkyl group substituted by ahalogen atom; a naphthyl group; a pyridyl group or a pyridyl groupsubstituted by a lower alkyl group, and a suitable carrier.
 2. Afungicidal composition according to claim 1, wherein said composition isused for seed treatment.
 3. A fungicidal composition according to claim1 or 2, wherein the ketene S,S-acetal derivative is2-(1-imidazolyl)-2-[4-(2-chlorophenyl)-1,3-dithiolan-2-ylidene]acetonitrile(E isomer).
 4. A fungicidal composition according to claim 1 or 2wherein the ketene S,S-acetal derivative is2-(1-imidazolyl)-2-[4-(2,4-dichlorophenyl)-1,3-dithiolan-2-ylidene]acetonitrile(E-isomer).
 5. A fungicidal composition according to claim 1 or 2,wherein the ketene S,S-acetal derivative is2-(1-imidazolyl)-2-[4-(2-bromophenyl)-1,3-dithiolan-2-ylidene]acetonitrile(E-isomer).
 6. A method for controlling fungal diseases of agriculturaland horticultural crop which comprises applying to said crops afungicidally effective amount of a ketene S,S-acetal derivativerepresented by the general formula (1) ##STR61## wherein R represents ahydrogen atom; an alkyl group having 1 to 8 carbon atoms; a cycloalkylgroup having 3 to 6 carbon atoms; a methylen group; a lower alkenylgroup; a lower alkyl group substituted by a halogen atom; a cyano group,a lower alkyloxyl group, a lower alkylthio group, a carbamoyl group, alower alkanoyl group, or analkenoyloxy group; a phenyl group representedby ##STR62## (in which R₁ represents a hydrogen atom, a halogen atom, astraight or branched chain lower alkyl group, a lower alkoxy group whichmay be substituted by one or more halogen atoms, a phenoxy group or amethylenedioxy group, and m represents an integer of 1 to 3); a benzylgroup, a methylenedioxybenzyl group; a phenoxyalkyl group; aphenoxyalkyl group substituted by a halogen atom; a naphthyl group; apyridyl group or a pyridyl group substituted by a lower alkyl group. 7.The method for controlling fungal diseases of agricultural andhorticultural crops according to claim 6, wherein said ketene is appliedto seed treatment.
 8. The method for controlling fungal diseases ofagricultural and horticultural crops according to claim 6 or 7, whereinthe ketene S,S-acetal derivative is2-(1-imidazolyl)-2-[4-(2-chlorophenyl)-1,3-dithiolan-2-ylidene]acetonitrile(E isomer).
 9. The method for controlling fungal diseases ofagricultural and horticultural crop according to claim 6 or 7, whereinthe ketene S,S-acetal derivative is2-(1-imidazolyl)-2-[4-(2,4-dichlorophenyl)-1,3-dithiolan-2-ylidene]acetonitrile(E isomer).
 10. The method for controlling fungal diseases ofagricultural and horticultural crop according to claim 6 or 7, where inthe ketene S,S-acetal is2-(1-imidazolyl)-2[4-(2-bromophenyl)-1,3-dithiolan-2-ylidene]acetonitrile(E isomer).
 11. A pharmaceutical composition for controlling mycosis,comprising a pharmaceutically effective amount of a ketene S,S-acetalderivative represented by the general formula (1) ##STR63## wherein Rrepresents a hydrogen atom; an alkyl group having 1 to 8 carbon atoms; acycloalkyl group having 3 to 6 carbon atoms; a methylene group; a loweralkenyl group; a lower alkyl group substituted by a halogen atom; acyano group, a lower alkoxyl group, a lower alkylthio group, a carbamoylgroup, a lower alkanoyl group, or an alkenoyloxy group; a phenyl grouprepresented by ##STR64## (in which R₁ represents a hydrogen atom, ahalogen atom, a straight or branched chain lower alkyl group, a loweralkoxyl group which may be substituted by one or more halogen atoms, aphenoxy group or a methylenedioxy group, and m represents an integer of1 to 3); a benzyl group, methylenedioxybenzyl group; a phenoxyalkylgroup; a phenoxyalkyl group substituted by a halogen atom; a naphthylgroup; a pyridyl group or a pyridyl group substituted by a lower alkylgroup, and a pharmaceutically acceptable carrier.
 12. The pharmaceuticalcomposition according to claim 11, wherein the active ingredient isformulated with a pharmaceutically acceptable diluent.
 13. Thepharmaceutical composition according to claim 11, wherein thecomposition is any form of solution, creams, suppositories, ointments,tablets.
 14. The pharmaceutical composition according to claim 11,wherein the ketene S,S-acetal derivative is2-(1-imidazolyl)-2-[4-(2,4-dichlorophenyl)-1,3-dithiolan-2-ylidene]acetonitrile(E isomer).
 15. The pharmaceutical composition according to claim 11,wherein the ketene S,S-acetal derivative is2-(1-imidazolyl)-2-[4-(2-chlorophenyl)-1,3-dithiolan-2-ylidene]acetonitrile(E isomer).
 16. The pharmaceutical composition according to claim 11,wherein the ketene S,S-acetal derivative is2-(1-imidazolyl)-2-[4-(2-bromophenyl)-1,3-dithiolan-2-ylidene]acetonitrile(E isomer).